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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 2  |  Issue : 3  |  Page : 222-227

SARS-CoV-2 viral load: Implication in COVID-19 pathogenesis, clinical presentation, diagnosis, treatment, prognosis and infectivity


Department of Internal Medicine, (Division of Infectious Disease), All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

Date of Submission09-Oct-2020
Date of Decision29-Jan-2021
Date of Acceptance27-Mar-2021
Date of Web Publication04-Jun-2021

Correspondence Address:
Dr. Prasan Kumar Panda
Department of Internal Medicine, Division of Infectious Disease, All India Institute of Medical Sciences, Rishikesh, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JME.JME_134_20

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  Abstract 


The SARS-CoV-2 viral load may have importance in assessing COVID-19's pathogenesis, clinical presentation, diagnosis, treatment, prognosis and infectivity. The severity of the disease has been attributed to the dysregulated immune mechanisms, but studies have suggested a correlation between disease severity and viral loads although evidence is not strong enough in justifying the same. Viraemia is shown to be keenly related to the disease progression. Viraemia has an association with increased Interleukin-6 levels and poorer prognosis. In terms of symptomatology, any definite correlations are not yet deduced, with no difference in viral loads among symptomatic and asymptomatic individuals. Reduction of viral load may be used as a marker of treatment success. Cycle threshold (Ct) values correlate with the SARS-CoV-2 viral loads. Ct values have shown a correlation with viral cultures and sub-genomic RNA values, both of which are considered the gold standard for determining infectivity but are expensive. Thereby, Ct value titres form an economical basis for deciding the de-isolation of the patients, which has implications in better resource management. Various limitations of viral load testing, especially of Ct values including human and laboratory factors are also discussed.

Keywords: Coronavirus, cycle threshold, cytokine storm, nasopharyngeal swab, viremia


How to cite this article:
Kapoor M, Panda PK. SARS-CoV-2 viral load: Implication in COVID-19 pathogenesis, clinical presentation, diagnosis, treatment, prognosis and infectivity. J Med Evid 2021;2:222-7

How to cite this URL:
Kapoor M, Panda PK. SARS-CoV-2 viral load: Implication in COVID-19 pathogenesis, clinical presentation, diagnosis, treatment, prognosis and infectivity. J Med Evid [serial online] 2021 [cited 2022 Jan 24];2:222-7. Available from: http://www.journaljme.org/text.asp?2021/2/3/222/333966




  Introduction Top


Coronaviruses are single-stranded RNA viruses, having the largest genome among all the RNA viruses.[1],[2] As with other viral infections, diagnosis is determined by the detection of the virus in laboratories by various assays like reverse transcription-polymerase chain reaction (RT-PCR). Viral infections such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and cytomegalovirus have a defined criterion of severity based on their viral loads. HIV viral load is associated with lower CD4 counts, severe immunosuppression and severe clinical features, and treatment success is judged by serial assessment of decline in the viral load.[3] Similarly, HCV RNA viral load is an important test as it forms the basis for the treatment initiation and analysing the success of treatment. Coronavirus may share the same characteristics. With the recent outbreak of COVID-19 disease, it is rational to discuss various aspects of viral loads for clinical implications.

In this mini-review, we want to correlate SARS-CoV-2 viral loads to COVID-19 pathogenesis, clinical presentation, diagnosis, treatment, prognosis and infectivity and will compare these with some other viruses that will update recent advances and provoke researchers to find answers through large studies ahead.


  SARS-CoV-2 Viral Load Top


Real-time RT-PCR assay is the recommended test for the determination of the SARS-CoV-2 virus. Oligonucleotide primers/probes to detect viruses are selected from the nucleocapsid (N) gene region.[4] Viral load/titre is the quantification of the virus in the body fluid. Unlike other above mentioned viruses, exact quantification is not possible for SARS-CoV-2 at this point; however, semi-quantification has already started and is providing the same clinical importance. Cycle threshold (Ct) values of RT-PCR are a viral copy number indicator. The lower Ct value corresponds to a high copy number, i.e., high viral load as few cycles of PCR are required to detect organisms if a greater number of viruses are there in the body fluid. Ct <40 is considered positive for SARS-CoV-2. Nasal swabs had a mean Ct value 24.3 (1.4 × 106 copies/mL) compared with >30 (<2.6 × 104 copies/mL) in other specimens, indicating higher viral loads in this specimen.[5] We will discuss the role of viral load under various headings below.


  Implications in Pathogenesis Top


Serum SARS-CoV RNA detection (RNAaemia) is diagnosed only in critically ill patients. RNAemia has an association with increased Interleukin-6 (IL-6) levels and poorer prognosis. Elevated IL-6 is a component of a large cytokine storm, which leads to the worsening of outcomes. The severity of the disease is attributed to the dysregulated immune mechanisms. However, many studies have suggested a direct correlation between disease severity and high viral loads. Still, the evidence is not strong enough in justifying the direct correlation between viral load and infectivity or severity. Among other things, the sampling time since illness onset must be controlled while comparing Ct values between mild and severe disease.[6],[7],[8] The timeline of symptomatology in SARS-CoV 2003 is characteristic and important. Flu-like symptoms (fever, muscle aches, etc.) were seen in the 1st week, corresponding to an increase in viral loads, suggesting that this was the effect of viral multiplication and cell lysis. However, 2nd-week characteristics showed diarrhoea and oxygen desaturation with flitting radiological patterns; this also marks the immunoglobulin G seroconversion and fall in viral load. Then, a question arises, why there is a progression in symptoms despite a fall in viral loads? This can be explained by the fact that the disease progression may be because of host dysregulated immunopathological response, i.e. sepsis rather than just an increase in the viral loads.[9] Adenovirus, respiratory syncytial virus (RSV) and rotavirus also report viraemia, with serum adenovirus DNA titres being related to mortality rates.[10] With time, we may find these types of associations with COVID-19 disease.


  Implications in Clinical Presentation Top


Viraemia in the severely affected group is negatively correlated with lymphocyte counts (CD4, CD8). This suggests that a decrease in lymphocyte numbers directly affected by viraemia is keenly related to disease progression.[11] SARS-CoV-2 RNA load is positively correlated with IL-2 receptor level, prothrombin time, lactate dehydrogenase and troponin T levels in patients with COVID-19 indicating that viral loads directly correlate with organ damage and resulting symptomatology.[12] Some studies have also demonstrated no difference in viral loads amongst symptomatic and asymptomatic individuals, hence a definite correlation cannot be deduced between viral loads and symptomatology as of yet.[13] Furthermore, primary and secondary transmissions usually lead to symptomatic COVID-19, whereas tertiary transmissions lead to asymptomatic infection, but with more infectivity.[14] The reason for these atypical findings is not clear, maybe, in future studies, it would be appropriate to see the role of viral loads on these transmission types.


  Implications in Diagnosis Top


Being a respiratory pathogen, samples collected include nasal, mid-turbinate, nasopharyngeal, oropharyngeal swabs or sputum. RT-PCR converts RNA into DNA (complementary DNA) and amplifies-specific DNA targets using PCR.[15] In this process, the Ct value is the number of cycles required for the fluorescent signal to cross the threshold (exceed the background level).[16] Ct values are inversely proportional to the amount of target nucleic acid in the sample (a lower Ct value means a higher amount of target nucleic acid in the sample). Ct <40 is considered positive for SARS-CoV-2.[17] Samples of sputum may show greater viral loads than the throat samples (sputum-17429 ± 6920 copies/test, throat-2552 ± 1965 copies/test, nasal swabs-651 ± 501 copies/test).[18],[19],[20],[21] Between nasopharyngeal and oropharyngeal swabs, the former are considered better as their yields are higher and it is safer for the healthcare worker to collect. In scarce conditions and in asymptomatic patients who want the testing just because of the scare, a self-collected saliva/nasal wash sample may be used as an alternative.[22] Self-collected salivary collections are reported to be concordant with nasopharyngeal specimens in 91% of patients, some studies showing upto a 100% concordance rate.[23],[24] About 60% of patients had the virus detected in stool samples also, compared to 41% detection in serum. In general, nasopharyngeal swabs are taken to demonstrate cure, but their efficiency for the same remains questionable.[25] The virus stays in the stools for a longer time (22 days) as compared to respiratory (18 days) and serum samples (16 days).[26] Stool samples must be equally considered infective as the respiratory samples. The highest viral loads are seen within 1st week or about 5 days after symptom onset. Loads can range from 104 to 107 copies/millilitre. Posterior oropharyngeal saliva has the highest loads in the first 7 days. 33% of patients may show prolonged virus detection (>20 days), although no association was there between prolonged detection and severity of illness. Increasing age was also associated with higher viral loads.

Viruses including RSV and influenza are detectable for a short time only and a positive test is indicative of active infection. SARS-CoV-2 can show positive results for a prolonged duration despite being clinically asymptomatic also.[27]


  Implications in Treatment Top


No treatment has been definitive in the management of COVID-19 as of yet. However, various trials are being conducted with possible targets. Hydroxychloroquine demonstrated anti-SARS-CoV-19 activity in vitro.[28] In a study by Gautret et al., all hydroxychloroquine and azithromycin-treated patients showed virologic cure at day 6, compared with 57% cure in controls.[29] Another drug combination considered was lopinavir-ritonavir, although SARS-CoV-2 viral loads did not show any significant differences as compared with standard care.[30] Lopinavir–ritonavir or IF-beta-1b were shown to reduce lung injury and viral loads in primate models of MERS-CoV.[31] The 2003 SARS-CoV RNA loads got significantly elevated upon hydrocortisone treatment in the 2nd–3rd weeks, suggesting that the use of steroids as per acute respiratory distress syndrome protocols may be questionable in these viruses.[32] This being said, steroids are the only group of drugs showing significant promise in the management of COVID-19.[33] Mostly around hospital admission, the viral load titres have peaked, hence anti-viral resistance can develop just like in influenza treatment by a single-drug regime (amantadine, a neuraminidase inhibitor, etc.). In influenza, triple-drug combinations improved the prognosis and decreased the risk of resistance.[34] Multidrug regimes may be warranted in COVID-19 as seen by success in a recent trial.[35] Patients in the triple therapy group (lopinavir-ritonavir, ribavirin and interferon 'β-1 b)' only received interferon if they presented within 7 days of symptom onset. The time to negative nasopharyngeal swab tests was significantly shorter in the combination therapy group (7 vs. 12 days) along with better clinical outcomes, including shorter time to symptom alleviation (4 vs. 8 days) and shorter median hospital stay (9 vs. 15 days). IL-6 also holds potential as a therapeutic target in critical patients.[36] A South Korea-based company has reported promising results from the preclinical tests of its COVID-19 antibody treatment, which led to a 100-fold decrease in the viral loads of SARS-CoV-2.[37] Patients taking arbidol showed a lesser duration of a positive RNA test in comparison to the lopinavir/ritonavir group.[38] With time, we will get more updates on viral loads with respect to treatment effect.


  Implications in Prognosis Top


Differential Ct values (Ctsample– Ctref) in severe cases were quite low as compared to mild ones. Severe cases have viral loads nearing 60x that of mild cases, suggesting that higher viral loads are associated with more severe disease.[39] A BMJ study also confirmed the same, severe disease had significantly higher viral loads than the mild disease.[26],[40] However, viral loads were just 1 log10 higher in severe as compared to mild cases, hence the difference may not be that significant.[41] A study found that severe disease demonstrated virus shedding up to 35 days post-onset, whereas the mild group did not show any demonstrable loads post 15 days.[42] Patients with higher baseline viral loads may be more likely to suffer from the severe disease in the due course.[43] Viral load is higher in early and gets reduced in recovery stages.[21] IL-6 levels of critical groups were seen to be significantly high, about 10 times compared with others. These extreme IL-6 levels had a close relation with RNAemia detection.[44] This suggests the possibility of the association of viraemia with the severity of the disease. As already known, high IL-6 levels are the hallmark and deciding force of the cytokine storm,[45] responsible for multi-organ dysfunction among critical patients. Significantly, COVID viral loads and mortality were independently associated. There was about a 7% increase in hazard proportionate to each log transformed copy per millilitres.[46] The correlation of viral loads with severity holds for other viruses also like HIV, HBV and the SARS-CoV 2003, which is a member of the coronavirus family. About 90% of mild patients cleared the virus early (about 10 days), compared to severe cases, which remained positive on day 20.[47] The viral loads in SARS-CoV 2003 were also related to their mortality and adverse intensive care unit outcomes.[48],[49]


  Implications in Infectivity Top


SARS-CoV-2 bears quite a high infectivity, having a basic reproductive number (number of cases generated by one case) 2.2–2.5 (in Wuhan). The serial interval (time between the symptomatic onset of successive cases) was approximately 6 days. Infectivity starts about 2 days before any symptoms arise and peaks about 0.7 days before symptomatology begins.[50] Asymptomatic transmission is estimated to be 44%.[50] Higher viral loads, as demonstrated by low Ct values, can be taken as indicators of infectivity.[51],[52] Mere RT-PCR detection of the virus cannot be taken as an indicator of infective potential.[16] As mentioned before, viral loads in the form of Ct values better correlate with the same. SARS-CoV-2 Vero cell infectivity could only be observed for Ct values <24 and symptom onset to test duration <8 days. Infectivity of patients with Ct >24 and duration of symptoms >8 days may be less. This is important in guiding public health policy and the clinical, infection control, and occupational health decisions.[53]

On different surfaces, viral titres show different trends. A fifty-percent tissue culture infective dose (TCID50) is used to measure the infectious virus titre. This is an endpoint dilution assay that quantifies the virus amount which is required for the killing of 50% of the infected hosts or to produce a cytopathic effect in 50% of the inoculated tissue culture cells.[54] Plastic showed a decrease in titres from 103.7 to 100.6 TCID50/ml in 3 days, whereas steel showed the transition from 103.7 to 100.6 TCID50/ml in 2 days. Copper was different, with no viable SARS-CoV-2 virus recovered after 4 h in comparison to 8 h for CoV-1. However, the stability of SARS-CoV-1 was comparable to CoV-2. For cardboard, the timing was 24 h for SARS-CoV-2 and 8 h for CoV-1.[55] No infectious virus was detected from the paper after 3 h and on wood or cloth on the 2nd day. SARS-CoV-2 is stable on a smooth surface. No infectious virus was recovered from glass and banknotes (day-4), steel and plastic (day-7). Importantly, infectious viruses (∼0·1% original titre) may be recovered from the outer layer of the surgical mask on day 7 also.[56]

Viral culture is the definitive answer in the determination of the viability of the virus. A German study revealed that no viral isolates could be obtained from nasopharyngeal samples after 8 days despite high viral loads.[47] Confirmation was done by viral replicative RNA intermediates or sub-genomic (sg) mRNAs, which are only present in actively infected cells and are not packaged into virions. Sputum sgRNA values declined over days 10–11, whereas throat swab sgRNA levels were undetectable after 5 days, implying loss of infectivity. This is in contrast to the persistent viral PCR positivity from these specimens. Viral culture and sgRNA determination are not possible in each hospital and not economically viable for general public use. Another study from France showed a significant relationship between Ct value and viral culture positivity rates. Samples with Ct value of 13–17 had positive culture growths. Culture positivity rates declined progressively with the rise in Ct values to reach 12% at 33 Ct value and no culture being obtained from samples with Ct >34.9.[57]

SARS-CoV-2 has infectiousness similar to influenza because SARS-CoV-2 transmissibility also peaked on or before symptom onset, hence isolation and quarantine measures need a review.[9],[50],[58],[59],[60]


  Cost-effectiveness and Management Implications Top


Viral load determination is a very effective way to follow-up the COVID-19 infection course. Although viral culture as described is in every way a better test for the calculation of infectivity, it is not used routinely. Owing to the higher costs, it is only used as a research tool. Hence, worldwide viral load testing in the form of Ct values is popularly used. This has important implications in the management as well. Patients having higher viral loads, or lower Ct values may be given priority for hospital admissions and advised strict isolation, keeping in mind the possibility of more severe disease and higher infectivity. Ct values may be used as a cut-off for deciding the de-isolation of COVID-19-positive patients.[16]


  Pitfalls of Viral Load Top


Host factors

The severity of the disease is affected by the underlying comorbidities and genetic makeup of the host. Hence, viral loads affecting the severity exactly cannot be assessed until exact matching controls are taken. The Ct values can also vary depending on the kind of specimens collected from the same person. For instance, nasopharyngeal and oropharyngeal samples collected from the same person can have different viral loads, making the Ct value a less reliable measure to assess a person's infectiousness or disease severity. Furthermore, the amount of virus present in nasopharyngeal and oropharyngeal samples can vary when collected at different times even on a single day.

Laboratory factors

Various samples yield different viral loads from the same individual. Hence, a single viral load titre is unacceptable as a marker of disease severity. Instead, serial viral load monitoring can be a better marker of disease progression. Most samples have human DNA, epithelia, or leucocytes as contaminants. Different PCR methods can lead to different results too. A particular RNA/DNA sample can give different results depending upon target sequences, reverse transcriptase and environmental conditions. The cut-off value of Ct in PCR has to be defined properly. Another limitation is that the Ct value trends and cut-offs can vary laboratory to laboratory depending upon the test conditions and equipment used, hence no standardisation can be there.

Technical factors

The viral load values can vary depending on how the samples have been collected. Poorly collected nasopharyngeal or oropharyngeal swabs can have very high Ct values, thus leading to incorrect conclusions about infectiousness or disease severity. Ct values are also determined by the technical competence of the person performing the test and the analytical skills of the interpreter.

Multiple infections

It is often seen that in cases of multiple viral infections, the viral load of a single virus is reduced.[27] Viral loads in single-infections with rhinovirus, coronavirus and parainfluenza virus were higher than for the same virus in multiple infections. Children with RSV-Rhinovirus multiple infections showed that more severe disease can correlate with lower loads of rhinovirus. This suggests these viruses may be the bystanders in multiple infections.[27]

Types of measurement

As mentioned previously, viral cultures instead of Ct values are the gold standard to determine the infective potential of the virus. Even sg-mRNA levels are better as they correlate purely with the infective potential of the virus. However, both are available only in research settings. For common use, we have to rely on Ct value which needs more standardisation.


  Conclusion Top


Based on preliminary analysis, it can be concluded that viral loads are important in analysing various aspects of SARS-CoV-2 viral infection. Higher viral loads may lead to stronger immune system activation including cytokine storm. Hence, drugs modifying the immune system need to be considered in the management of COVID. The disease severity has been attributed to the dysregulated immune mechanisms, but the evidence is not strong enough in justifying a correlation between disease severity and viral loads. Viraemia is shown to be keenly related to the disease progression. It has an association with increased IL-6 levels and poorer prognosis. There is no difference in the viral loads amongst symptomatic and asymptomatic individuals. The viral load may be used as a prognostic marker for the success of treatment. Ct values have shown a correlation with the viral cultures and sg-mRNA values, both of which are considered the gold standard for determining infectivity but costly and technology driven. Hence, Ct value titres form an economical basis for deciding the de-isolation of the patients, which has implications in better resource management. That being said, Ct values have limitations too, most important being the lab-to-lab variation and lack of standardisation. Still, it is an exciting area of focus in the ongoing COVID pandemic and all these measures can help in the containment of this pandemic.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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